title: HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury.
abstract: HIV-1 enters the central nervous system early in infection; although HIV-1 does not directly infect neurons, HIV-1 may cause a variety of neurological disorders. Neuronal loss has been found in HIV-1, but synaptodendritic injury is more closely associated with the neurocognitive disorders of HIV-1. The HIV-1 transactivator of transcription (Tat) protein causes direct and indirect damage to neurons. The cysteine rich domain (residues 22-37) of Tat is important for producing neuronal death; however, little is known about the effects of the Tat protein functional domains on the dendritic network. The ability of HIV-1 Tat 1-101 Clades B and C, Tat 1-86 and Tat 1-72 proteins, as well as novel peptides (truncated 47-57, 1-72δ31-61, and 1-86 with a mutation at Cys22) to produce early synaptodendritic injury (24h), relative to later cell death (48h), was examined using cell culture. Treatment of primary hippocampal neurons with Tat proteins 1-72, 1-86 and 1-101B produced a significant early reduction in F-actin labeled puncta, implicating that these peptides play a role in synaptodendritic injury. Variants with a mutation, deletion, or lack of a cysteine rich region (1-86[Cys22], 1-101C, 1-72δ31-61, or 47-57) did not cause a significant reduction in F-actin rich puncta. Tat 1-72, 1-86, and 1-101B proteins did not significantly differ from one another, indicating that the second exon (73-86 or 73-101) does not play a significant role in the reduction of F-actin puncta. Conversely, peptides with a mutation, deletion, or lack of the cysteine rich domain (22-37) failed to produce a loss of F-actin puncta, indicating that the cysteine rich domain plays a key role in synaptodendritic injury. Collectively, these results suggest that for Tat proteins, 1) synaptodendritic injury occurs early, relative to cell death, and 2) the cysteine rich domain of the first exon is key for synaptic loss. Preventing such early synaptic loss may attenuate HIV-1 associated neurocognitive disorders.
authors.affiliation: Laboratory Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina, Barnwell College Building, 1512 Pendleton Street, Columbia, SC 29208, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bertrand
authors.forename: Marina V
authors.initials: MV
authors.lastname: Aksenova
authors.forename: Charles F
authors.initials: CF
authors.lastname: Mactutus
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Booze
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus; D003545:Cysteine
keywords: Clade B; Clade C; F-actin; HAND; Primary cell culture; Rat